Novel 6-phenyl and substituted 6-phenyl-1,2,4-triazolo[4,3-b]pyridazines

ABSTRACT

This disclosure describes novel 6-phenyl and substituted 6-phenyl-1,2,4-triazolo[4,3-b]pyridazines and their use as anxiolytic agents.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly,is concerned with novel 6-phenyl and substituted6-phenyl-1,2,4-triazolo[4,3-b]pyridazines which may be represented bythe following structural formula: ##STR1## wherein R₁ is selected fromthe group comprising, CHO, CH₂ Cl, CHCl₂, CCl₃, CH₂ OH, CH₂ O-loweralkyl (C₁ -C₃), CH₂ F, CHF₂, CF₃, CN and CO₂ -lower alkyl (C₁ -C₃); R₂is selected from the group consisting of hydrogen, fluoro, chloro andtrifluoromethyl.

DESCRIPTION OF THE INVENTION

The 6-phenyl and substituted 6-phenyl-1,2,4-triazolo[4,3-b]pyridazinesof the present invention are in general, colorless, tan or pale yellowcrystalline solids having characteristic melting points and spectralproperties. They are soluble in organic solvents such as lower alkanols,dimethylsulfoxide, and N,N-dimethylformamide. They are, however,generally insoluble in water.

The 3-monohalomethyl, 3-dihalomethyl and3-trihalomethyl-1,2,4-triazolo[4,3-b]pyridazines of this invention areprepared by reaction of 6-phenyl and substituted6-phenyl-3-hydrazinopyridazines with mono, di or tri chloro or fluoroacetic acids or with mono, di or tri chloro or fluoro acetyl chlorides.Alternatively, the 6-phenyl and substituted6-phenyl-3-hydrazinopyridazines are reacted with mono, di or tri chloroor fluoro acetic anhydrides to give the products of the invention.

Products containing a 3-monohalomethyl, 3-dihalomethyl and a3-trihalomethyl substituent are prepared as shown in Schemes I, where Xis chloro and fluoro and R₂ is as previously defined. ##STR2##

The novel 3-lower alkoxymethyl 1,2,4-triazolo[4,3-b]pyridazines of thisinvention are prepared by reaction of a 3-halomethyl derivative II withthe anion of a lower alkanol (R₃ OH) wherein R₃ is a lower alkyl groupof one to 3 carbon atoms in an inert solvent or preferably in excesslower alkanol as solvent. Alternatively, a lower alkoxy acetyl chlorideor anhydride is reacted with a 6-phenyl or substituted-phenyl3-hydrazinopyridazine (I) to give the products of formula V as shown inScheme II. Products of this invention wherein R₁ is --CO₂ lower alkyl(C₁ -C₃) are prepared by reaction of a 3-hydrazinopyridazine of formulaI with a lower alkyl (C₁ -C₃) oxalyl chloride to give the derivatives offormula VI. ##STR3## Novel compounds of this invention wherein R₁ is CH₂OH and CHO may be prepared as shown in the above reaction schemes.Reaction of a 3-halomethyl derivative II wherein X is halogen withaqueous base or with water under solvolytic conditions in the presenceof silver nitrate gives the 3-hydroxymethyl derivatives VII.Alternatively, 3-lower alkoxy carbonyl derivatives VI may be reducedwith appropriate metal hydrides or sodium in liquid ammonia to give thenovel compounds VII. Oxidation of 3-hydroxymethyl derivatives VII withdimethyl sulfoxide-acetic anhydride and similar reagents gives the3-carboxaldehyde compounds VIII. Reaction of3-halomethyl-1,2,4-triazolo[4,3-b]pyridazines of structural formula IIwith dimethyl sulfoxide in the presence of a base such as pyridine givesthe 3-carboxaldehyde derivatives VIII.

The novel compounds of the present invention possess central nervoussystem acitivity at non-toxic doses and as such are useful as anxiolyticagents. That is, they produce certain responses in standard tests withlaboratory animals which are known to correlate well with relief ofanxiety in man.

The anti-anxiety properties of the novel compounds of the presentinvention have been established in a test which indicates anxiolyticactivity by the measure of protection from convulsions resulting fromthe administration of pentylenetetrazole. Single or graded dose levelsof the test compounds were administered orally or intraperitoneally in a2% starch vehicle, containing 0.5% v/v polyethylene glycol and one dropof polysorbate 80 to groups of at least 4 rats. At 30 or 60 minutes, therats were treated intravenously with pentylenetetrazole at a dose of 23mg./kg. of body weight. This dose is estimated to cause clonic seizuresin 99% of unprotected rats. The test compounds are considered active ifthey protect 50% or more of the rats from clonic seizures. It has beenreported [R. T. Hill and D. H. Tedeschi, "Animal Testing and ScreeningProcedures in Evaluating Psychotropic Drugs" in "An Introduction toPsychopharmacology", Eds. R. R. Rech and K. E. Moore, Raven Press, NewYork, pp. 237-288 (1971)] that there is a high degree of correlationbetween antagonism of pentylenetetrazole seizures in rats andanti-anxiety effects in higher warm-blooded animals. The followingrepresentative compounds of the present invention have been shown topossess anxiolytic activity when tested as described above.

3-(Methoxymethyl)-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine

3-(Methoxymethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine

BRAIN-SPECIFIC BENZODIAZEPINE RECEPTOR BINDING ASSAY

Another test utilized for the determination of anxiolytic activity isthe measurement of the ability of test compounds to inhibit the bindingof tritiated benzodiazepines to brain-specific receptors of warm-bloodedanimals. A modification of the method described by R. F. Squires et al.Nature, 266, No. 21, pg. 732, (April, 1977) and H. Mohler et al.Science, 198, pg. 849, (1977) was employed.

Male albino rats (Wistar strain, weighing 150-200 g. each) were obtainedfrom Royalhart Farms. ³ H-Methyl-diazepam (79.9 Ci/mmol) and ³H-methylflunitrazepam (84.3 Ci/mmol) were obtained from New EnglandNuclear. The test compounds were solubilized in eitherdimethylformamide, acetic acid, ethanol or hydrochloric acid.

Whole cortex of rats was homogenized gently in 20 volumes of ice-cold0.32 M. sucrose, centrifuged twice at 1000 g for 10 minutes and thenrecentrifuged at 30,000 g for 20 minutes to produce a crude P₂-synaptosomal fraction. The P₂ -fraction was either: (1) resuspended intwice the original volume in hypotonic 50 mM. Tris.HCl (pH 7.4), or (2)resuspended in one-half the original volume in hypotonic 10 mM. Tris.HCl(pH 7.4) and frozen (-20° C.) until time of use. Frozen P₂ preparationswere thawed and resuspended in four times the original homogenizingvolume at time of assay.

The binding assay consisted of 300 μl. of the P₂ -fraction suspension(0.2-0.4 mg. protein), 100 μl. of test drug and 100 μl. of ³ H-diazepam(1.5 nM., final concentration) of ³ H-flunitrazepam (1.0 nM., finalconcentration) which was added to 1.5 ml. of 50 mM. Tris.HCl (pH 7.4).Non-specific binding controls and total binding controls received 100μl. of diazepam (3 μM. final concentration) and 100 μl. of deionizedwater, respectively, in place of the test compound. Incubation for 30minutes proceeded in ice and was terminated by filtration, under vacuum,through Whatman GF/C glass fiber filters. The filters were washed twicewith 5 ml. of ice-cold 50 mM. Tris.HCl (pH 7.4) and placed inscintillation vials. After drying at 50°-60° C. for 30 minutes, 10 ml.of Beckman Ready-Solve HP was added and the radioactivity determined ina Beckman Scintillation Counter.

Compounds which exhibited the ability to inhibit ³ H-benzodiazepinebinding by ≧20% were considered to be active. Inhibition of binding wascalculated by the difference between total binding and binding in thepresence of test compound, divided by the total binding, X 100.

Representative compounds of the present invention which are active whentested by the ³ H-benzodiazepine binding assay are:

3-(Chloromethyl)-6-phenyl-1,2,4-triazolo[4,3-a]pyridazine

3-(Chloromethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine

The compounds of the present invention may be administered towarm-blooded animals orally or parenterally, if desired and when soadministered, may be considered as tranquilizing agents fortherapeutically desirable treatment of anxiety in warm-blooded animals.

The dosage regimen can be adjusted to provide optimum therapeuticresponse. Thus, for example, several doses may be administered daily, orthe dose may be reduced proportionately as indicated by the requirementsof the particular therapeutic situation.

For therapeutic administration, the compounds of this invention may beincorporated with pharmaceutical carriers such as excipients and used,for example, in the form of tablets, troches, dragees, capsules,suspensions, emulsions, liquids, syrups, wafers, chewing gum or the likefor oral administration.

Parenteral solutions and suspensions may be prepared for intramuscularor subcutaneous administration, and suppositories may be prepared forrectal administration. Such compositions and preparations should containat least 0.1% of active component. The percentage in the compositionsand preparations may, of course, be varied and may conveniently bebetween 2% to about 75% or more of the weight of the unit. The amount ofanxiolytic active component in such therapeutically useful compositionsor preparations is such that a suitable dosage of from about 3 mg. toabout 100 mg./kg./day will be obtained.

Preferred compositions or preparations according to the presentinvention are prepared so that an anxiolytic dosage unit form containsbetween about 1.0 mg. and 100 mg. of the therapeutically activecomponent.

The compositions of this invention are physiologically active asanxiolytic agents. As such, they can be incorporated in variouspharmaceutical forms such as set forth immediately above, for immediateor sustained release, by combining with suitable pharmaceuticalcarriers. They may be in the form of dosage units for a singletherapeutic dose or in small units for multiple dosages or in largerunits for division into single doses.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially non-toxic in theamounts employed.

SPECIFIC DISCLOSURE

The following specific examples illustrate the preparation of thecompounds of the present invention.

EXAMPLE 13-(Chloromethyl)-6-[3-(trifluoromethyl)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 80.0 g. of 3-chloro-6-[3-trifluoromethyl)phenyl]pyridazine(prepared as in Example 11 of U.S. Pat. No. 4,112,095), 150 ml. ofhydrazine monohydrate and 800 ml. of n-butyl alcohol is refluxed for 18hours. The reaction mixture is concentrated free of solvent. The solidconcentrate is filtered and washed with hexane several times to provide110.0 g. of 3-hydrazino-6-[3-(trifluoromethyl)-phenyl]pyridazine as acream colored solid.

To a chilled mixture of 17.5 g. of the preceding product in 300 ml. oftetrahydrofuran is added dropwise 5.48 ml. of chloroacetyl chloride. Thereaction mixture is allowed to warm to room temperature and is stirredfor 16 hours. The mixture is diluted with ether and filtered to collecta solid. The solid is stirred with saturated sodium bicarbonatesolution, collected by filtration, and washed with water anddichloromethane to give 19.0 g. of2-[6-(3-Trifluorophenyl)-3-pyradazinyl]hydrazide chloroacetic acid ascream colored crystals, m.p. 119°-121° C.

A mixture of 3.2 g. of the preceding compound and 50 ml. of glacialacetic acid is heated at reflux temperature for 3 hours. The solvent isremoved in vacuo and the residue is dissolved in dichloromethane. Thissolution is filtered through a column of hydrous magnesium silicate. Theeluent is concentrated, diluted with petroleum ether, cooled andfiltered to yield 0.8 g. of the product of the Example as whitecrystals, m.p. 183°-185° C.

EXAMPLE 2 3-(Chloromethyl)-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine

To a mixture of 16.9 g. of 3-hydrazine-6-phenyl-pyridazine in 250 ml. oftetrahydrofuran chilled in an ice bath, is added portionwise over 30minutes, 7.24 ml. of chloroacetyl chloride in 50 ml. of tetrahydrofuran.After stirring one hour, the mixture is allowed to warm to roomtemperature and is stirred for 3 hours. The solvent is removed underreduced pressure and the residue partitioned between ether and saturatedsodium bicarbonate solution. The mixture is filtered and the solidwashed with sodium bicarbonate solution and with water to give 23 g. ofa solid. The solid is recrystallized from dichloromethane-hexane to give8.9 g. of crystals identified as 2-(6-phenyl-3-pyridazinyl) chloroaceticacid hydrazide, m.p. 133°-134° C.

A 24.65 g. amount of the preceding product prepared as described aboveand 300 ml. of acetic acid is heated at 145° C. for one hour. Themixture is treated with activated carbon and filtered. The solvent isremoved and the residual oil is triturated with ether to give a solidwhich is filtered and washed with ether. The solid is dissolved indichloromethane and filtered through a column of hydrous magnesiumsilicate. The eluent (first cut) gives 7.43 g. of crude product. Asample is purified by thick layer chromatography on a silica gel plateto give the product of the Examples as a solid which is recrystallizedfrom dichloromethane-hexane to give crystals, m.p. 165°-166° C.

EXAMPLE 3 3-(Methoxymethyl)-6-phenyl-1,2,4-triazolo[4,3b]pyridazine

To a solution of 0.89 g. of sodium methoxide in 200 ml. of methylalcohol is added 3.4 g. of3-(chloromethyl)-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine. The reactionmixture is heated at reflux temperature for 18 hours then is treatedwith activated charcoal and filtered. The filtrate is evaporated to givea white solid. The solid is dissolved in methylene chloride and passedthrough a column of hydrous magnesium silicate. The eluent isconcentrated and diluted with hexane to give 3.0 g. of white crystals.Recrystallization from methylene chloride-hexane gives the product ofthe Example as white crystals, m.p. 133° C.

EXAMPLE 4 3-(Methoxymethyl)-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine

To a mixture of 0.01 mole of 3-hydrazino-6-phenylpyridazine in 25 ml. ofdioxane is added 0.005 mole of methoxyacetyl chloride. The mixture isrefluxed for 2 hours to give the product of the Example, m.p. 133° C.

EXAMPLE 53-(Methoxymethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 2.1 g. of3-(chloromethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazineand 0.40 g. of sodium methoxide in 50 ml. of ethanol is refluxed for 24hours. The solvent is removed under reduced pressure and the residue isdissolved in dichloromethane. The solution is filtered through a columnof hydrous magnesium silicate. The eluent is concentrated and hexaneadded to give 1.4 g. of the product of the Example as crystals, m.p.149°-150° C. Recrystallization from dichloromethane-hexane gives 0.6 g.of white crystals, m.p. 149°-151° C.

EXAMPLE 63-(Methoxymethyl)-6-[3-(trifluoromethyl)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine

To a mixture of 0.02 mole of3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine in 50 ml. of dioxaneis added 0.01 mole of methoxyacetyl chloride. The mixture is heated atreflux temperature for 4 hours, then is filtered. The filtrate isevaporated and the residue is crystallized from dichloromethane-hexaneto give the product of the Example, m.p. 149°-150° C.

EXAMPLE 76-(3-Fluorophenyl)-3-(methoxymethyl)-1,2,4-triazolo[4,3-b]pyridazine

As for Example 4, 6-(3-fluorophenyl)-3-hydrazinopyridazine (prepared ina manner similar to that described in Example 1) is reacted withmethoxyacetyl chloride to give the product of the Example.

EXAMPLE 86-(3-Chlorophenyl)-3-(methoxymethyl)-1,2,4-triazolo[4,3-b]pyridazine

As for Example 4, 6-(3-chlorophenyl)-3-hydrazinopyridazine (prepared asin Example 51 of U.S. Pat. No. 4,112,095) is reacted with methoxyacetylchloride to give the product of the Example.

EXAMPLE 93-(Chloromethyl)-6-(3-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

As for Example 2, 6-(3-fluorophenyl)-3-hydrazinopyridazine (prepared ina manner similar to that described in Example 1) is reacted withchloroacetyl chloride to give the product of the Example.

EXAMPLE 103-(Chloromethyl)-6-(3-chlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

As for Example 2, 6-(3-chlorophenyl)-3-hydrazinopyridazine is reactedwith chloroacetyl chloride to give the product of the Example.

EXAMPLE 11 6-Phenyl-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazine

To a mixture of 3.5 g. of 3-hydrazino-6-phenylpyridazine in 35 ml. ofpyridine is added dropwise 6.3 g. of trifluoroacetic anhydride. Themixture is refluxed for 6 hours, cooled and the solvent removed underreduced pressure. The residue is dissolved in ethyl acetate and passedthrough a pad of hydrous magnesium silicate. The eluent is concentratedto a dark solid which is recrystallized twice from ethanol to give 2.0g. of the product of the Example as crystals, m.p. 183°-184° C.

EXAMPLE 126-(3-Chlorophenyl)-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazine

As for Example 11, 6-(3-chlorophenyl)-3-hydrazinopyridazine is reactedwith trifluoroacetic anhydride in refluxing pyridine to give the productof the Example.

EXAMPLE 136-(3-Fluorophenyl)-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazine

As for Example 11, 6-(3-fluorophenyl)-3-hydrazinopyridazine is reactedwith trifluoroacetic anhydride in refluxing pyridine to give the productof the Example.

EXAMPLE 143-Cyano-6-[3-(trifluoromethyl)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 7.72 g. of3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine,17.6 ml. of N,N-diisopropylethylamine, 140 ml. of dioxane and 9.8 ml. ofbenzoyl chloride is heated at reflux temperature for 48 hours. Theresulting mixture is evaporated in vacuo and the residue is partitionedbetween water and dichloromethane. The organic layer is separated, driedover anhydrous sodium sulfate and evaporated to give a dark solid. Thesolid is heated with ethanol and the resulting mixture is filtered tocollect 10.6 g. ofα-{[6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methylenebenzyl alcohol, benzoate (ester) as crystals. Recrystallization frommethylene chloride gives cream colored crystals, m.p. 238°-240° C.

A mixture of 1.0 g. of the preceding compound, 10 ml. of water, 10 ml.of concentrated hydrochloric acid and 15 ml. of ethanol is heated on asteam bath for 18 hours. The mixture is cooled and filtered to collect asolid. The solid is washed with water to give 0.9 g. of off-whitecrystals. The material is recrystallized from ethanol-water to give 0.7g. of2-[6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazin-3-yl]acetophenoneas off-white crystals, m.p. 215°-218° C.

A 0.38 g. amount of the above product is dissolved in 5 ml. ofconcentrated sulfuric acid at room temperature, then 0.35 g. of sodiumnitrite is added and the mixture is allowed to stand at room temperaturefor one hour. The reaction mixture is poured into crushed ice/water andfiltered. The filter cake is washed with water and air dried to give 0.4g. of cream colored solid. The solid in 25 ml. of thionyl chloride isheated at the reflux temperature for 30 minutes then is allowed to standat room temperature for 2 hours. The reaction mixture is stripped ofvolatiles, cooled with cracked ice and made alkaline with concentratedammonium hydroxide. The mixture is extracted with methylene chloride.The combined extracts are dried over anhydrous sodium sulfate andevaporated to give 0.37 g. of a tan solid. The product is purifiedfurther by conventional preparative thin layer chromatography usingsilica gel plates and acetic acid/hexane (1:1) to afford a white solid.The solid is recrystallized from methylene chloride/hexane to give theproduct of the Example as white crystals, m.p. 184°-185° C.

EXAMPLE 156-[3-(Trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine-3-carboxylicacid, ethyl ester

To a suspension of 15.24 g. of3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine in 200 ml. oftetrahydrofuran, cooled in an ice bath is added dropwise, a solution of9.84 g. of ethyl oxalyl chloride in 50 ml. of tetrahydrofuran over 30minutes. The mixture is stirred at room temperature for 16 hours thenthe solvent is evaporated in vacuo. The residue is stirred withdichloromethane, and filtered. The solid is washed with dichloromethaneand with hexane to give 15.0 g. of2-[6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl]hydrazide oxalic acid,ethyl ester as a cream colored solid, m.p. 193°-196° C.

A mixture of the preceding compound (15.0 g.) in 175 ml. of glacialacetic acid is heated at reflux temperature for 1/4 hour and filteredthrough diatomaceous earth while hot. The filtrate is evaporated invacuo. The residue is dissolved in dichloromethane and this solution iswashed with an aqueous saturated sodium bicarbonate solution. Theorganic layer is dried over anhydrous sodium sulfate and the solvent isremoved. The resulting residue is dissolved in a minimum volume ofdichloromethane and hexane is added. Filtration gives 5.9 g. of theproduct of the Example as white crystals, m.p. 202°-204° C.

EXAMPLE 163-(Hydroxymethyl)-6-[3-(trifluoromethyl)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 2.3 g. of3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine, 188 g. of ethylglycolate and 40 ml. of n-butyl alcohol is heated at reflux temperaturefor 18 hours. The mixture is evaporated in vacuo. To the residue isadded dichloromethane and hexane. The mixture is filtered to give 2.0 g.of cream colored crystals. Recrystallization from ethyl acetate givesthe product of the Example as off-white crystals, m.p. 224°-226° C.

EXAMPLE 173-(Hydroxymethyl)-6-[3-(trifluoromethyl)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 7.76 g. of3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine, 6.66 g. ofhydroxyacethydrazide and 200 ml. of n-butyl alcohol is heated at refluxtemperature for 18 hours. The mixture is evaporated in vacuo and theresidue is triturated with dichloromethane-hexane. The mixture isfiltered and the solid is recrystallized from ethyl acetate to give theproduct of the Example as off-white crystals, m.p. 224°-226° C.

EXAMPLE 183-(Hydroxymethyl)-6-[3-(trifluoromethyl)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine

A 1.0 g. sample of3-(chloromethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazineis heated (50°-60° C.) in a mixture of acetone and water in the presenceof silver nitrate. The mixture is filtered and the filtrate concentratedto give the product of the Example.

EXAMPLE 193-(Trifluoromethyl)-6-(3-trifluoromethylphenyl)-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 1.4 g of3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine and 3.0 g. oftrifluoroacetic anhydride in 20 ml. of pyridine is refluxed for 16hours. The mixture is concentrated under vacuum and the residue treatedwith aqueous sodium bicarbonate solution. The mixture is filtered andthe solid dissolved in chloroform. The chloroform solution is dried overanhydrous sodium sulfate and hexane is added. Filtration gives 0.7 g. ofthe desired product as crystals, m.p. 189° C.

We claim:
 1. A compound selected from the group consisting of those ofthe formula: ##STR4## wherein R₁ is selected from the group comprisingCHO, CH₂ Cl, CHCl₂, CCl₃, CH₂ OH, CH₂ O-lower alkyl (C₁ -C₃), CH₂ F,CHF₂, CF₃, CN and CO₂ -lower alkyl (C₁ -C₃); R₂ is selected from thegroup consisting of hydrogen, fluoro, chloro and trifluoromethyl.
 2. Thecompound according to claim 1,3-(chloromethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine.3. The compound according to claim 1,3-(chloromethyl)-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine.
 4. Thecompound according to claim 1,3-(methoxymethyl)-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine.
 5. Thecompound according to claim 1,3-(methoxymethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]-pyridazine.6. The compound according to claim 1,3-(hydroxymethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]-pyridazine.